We seek to develop and characterize the world's only in-vivo model of human placentation under conditions of chronic hypoxia. Using the unique model of high altitude human pregnancy, the goal of this project is to examine the pathways by which hypoxia, in the absence of pathology, influences placental development and results in adaptation (i.e. normal growth) or fetal growth restriction. In vitro experiments show that oxygen plays a crucial role in early placental development and that both oxygen tension and the time at which it increases are key factors in determining the success of placentation. This data and clinical observations make it clear that hypoxia plays a major role in those pathologies involving abnormalities of placental development, such as intrauterine growth restriction and preeclampsia. Unfortunately, hypoxia is inevitably intertwined with under- or overlying pathologies and thus it has not been possible to investigate the role of hypoxia in placental development in vivo in the absence of pathology. We predict that the initial effect of chronic maternal hypoxia due to high altitude residence (3600 m) is reduction in trophoblast invasion of uteroplacental arteries, leading to a reduction in uteroplacental blood flow. Subsequent to this, our preliminary data suggest that there are two primary placental responses. The first is an up regulation of angiogenesis reflected in greater placental capillary density and increased release of angiogenic growth factors. The second is a decrease in placental nutrient transport and a consequent down-regulation of fetal growth and placental nutrient transport capacity. The aims of the project are to investigate these responses by determining whether, in high vs. low altitude pregnancy 1) there are increased circulating and placental markers of hypoxia, correlated with reduced trophoblast invasion and uteroplacental blood flow; 2) an increased angiogenic response, as evidenced by placental morphologic changes and increases in circulating and placental angiogenic growth factors, and 3) decreased nutrient transfer, decreased circulating growth factors and reduced placental nutrient transporter capacity. Gene array is used across all 3 aims to investigate 4 groups of specifically targeted and functionally essential genes 1) hypoxia-responsive genes, 2) gene markers of trophoblast invasion, 3) markers of angiogenesis and 4) nutrient transporters and transport regulators. This model will permit the development of a foundation upon which the etiology of various forms of IUGR can be explored. Such work will aid substantially in elucidating the pathologies that involve placenta hypoxia, e.g., preeclampsia, diabetes and IUGR.